Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Phosphine-Mediated Disulfide Metathesis in Aqueous Media
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2010 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 44, 8469-8471 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic carbohydrate systems have been efficiently generated through phosphine-mediated disulfide metathesis in aqueous media. The protein compatibility and binding features of the dynamic systems were demonstrated in situ using H-1 STD NMR.

Place, publisher, year, edition, pages
2010. Vol. 46, no 44, 8469-8471 p.
Keyword [en]
ORGANIC SULFUR CHEMISTRY, DYNAMIC COMBINATORIAL CHEMISTRY, EXCHANGE-REACTION, PHOSPHORUS NUCLEOPHILES, EQUILIBRIUM-CONSTANTS, INTERCHANGE REACTIONS, LIBRARIES, WATER, DESULFURIZATION, TRIPHENYLPHOSPHINE
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-13508DOI: 10.1039/c0cc03622fISI: 000283690400048Scopus ID: 2-s2.0-78049406031OAI: oai:DiVA.org:kth-13508DiVA: diva2:325942
Note
QC 20100621. Uppdaterad från manuskript till artikel (20101209).Available from: 2010-06-21 Created: 2010-06-21 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
Open this publication in new window or tab >>Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the design, formation and evaluation of dynamic systems constructed by means of sulfur-containing reversible reactions, in organic and aqueous media and under mild conditions.

In a first part, the synthesis of thioglycoside derivatives, constituting the biologically relevant starting components of the dynamic systems, is described. In addition, the pD-profile of the mutarotation process in aqueous media for a series of 1-thioaldoses is reported and revealed an astonishing beta-anomeric preference for all the carbohydrate analogs under acidic or neutral conditions.

In a second part, the phosphine-catalyzed or -mediated disulfide metathesis for dynamic system generation in organic or aqueous media is presented, respectively. The direct in situ 1H STD-NMR resolution of a dynamic carbohydrate system in the presence of a target protein (Concanavalin A) proved the suitability and compatibility of such disulfide metathesis protocols for the discovery of biologically relevant ligands.

In a third part, hemithioacetal formation is demonstrated as a new and efficient reversible reaction for the spontaneous generation of a dynamic system, despite a virtual character of the component associations in basic aqueous media. The direct in situ 1H STD-NMR identification of the best dynamic beta-galactosidase inhibitors from the dynamic HTA system was performed and the results were confirmed by inhibition studies. Thus, the HTA product formed from the reaction between 1-thiogalactopyranose and a pyridine carboxaldehyde derivative provided the best dynamic inhibitor.

In a fourth and final part, a dynamic drug design strategy, where the best inhibitors from the aforementioned dynamic HTA system were used as model for the design of non-dynamic (or “static”) beta-galactosidase inhibitors, is depicted. Inhibition studies disclosed potent leads among the set of ligands.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. 84 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2010:14
Keyword
Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.
National Category
Chemical Sciences Organic Chemistry Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-12414 (URN)978-91-7415-618-8 (ISBN)
Public defence
2010-05-12, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100621Available from: 2010-04-22 Created: 2010-04-20 Last updated: 2010-11-29Bibliographically approved
2. Dynamic Systems: Evaluation, Screening and Synthetic Application
Open this publication in new window or tab >>Dynamic Systems: Evaluation, Screening and Synthetic Application
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research work reported in the thesis deals with the development of dynamic covalent systems and their applications in evaluation and screening of protein-ligands and enzyme inhibitors, as well as in synthetic methodologies. The thesis is divided into four parts as described below.

In part one, synthetic methodologies to access 3-functionalized phthalides and 3-thioisoindolinones using the concept of cascade reactions are demonstrated. Efficient syntheses of the target products are designed and performed in one-pot process under mild reaction conditions.

 In part two, phosphine-catalyzed disulfide metathesis for the generation of dynamic carbohydrate system in aqueous solution is demonstrated. In the presence of biological target (Concanavalin A), the optimal dynamic ligand is successfully identified in situ by the 1H STD-NMR spectroscopy.

In part three, lipase-catalyzed resolutions of dynamic reversible systems using reversible cyanohydrin and hemithioacetal reactions in one-pot processes are demonstrated. The dynamic systems are generated under thermodynamic control in organic solution and subsequently resolved by lipase-mediated resolution under kinetic control. The resolution processes resulted in the lipase-selected substrates with high structural and stereochemical specificities.

In the last part, dynamic fragment-based strategy is presented using β-galactosidase as a model target enzyme. Based on our previous study, the best dynamic inhibitor of β-galactosidase was identified using 1H STD-NMR technique from dynamic hemithioacetal systems. The structure of the dynamic inhibitor is tailored by fragment linking and optimization processes. The designed inhibitor structures are then synthesized and tested for inhibition activities against β-galactosidase. 

 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. 69 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:33
Keyword
constitutional dynamic chemistry; dynamic combinatorial chemistry/ resolution; dynamic fragment-based approach; dynamic kinetic resolution; dynamic reversible systems; 1H STD-NMR; multicomponent reaction; tandem reaction
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-34100 (URN)978-91-7415-986-8 (ISBN)
Public defence
2011-06-07, F3, KTH, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
EU, European Research Council, MRTN-CT-2006-035614
Note
QC 20110526Available from: 2011-05-26 Created: 2011-05-25 Last updated: 2011-05-26Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textScopus

Search in DiVA

By author/editor
Caraballo, RémiSakulsombat, MorakotRamström, Olof
By organisation
Organic Chemistry
In the same journal
Chemical Communications
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 97 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf